Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Abstract

Long-term synaptic plasticity involves changes in the expression and membrane insertion of cell-surface proteins. Interestingly, the mRNAs encoding many cell-surface proteins are localized to dendrites, but whether dendritic protein synthesis is required for activity-induced surface expression of specific proteins is unknown. Herein, we used microfluidic devices to demonstrate that dendritic protein synthesis is necessary for activity-induced insertion of GluN2A-containing NMDA receptors in rat hippocampal neurons. Furthermore, visualization of activity-induced local translation of GluN2A mRNA and membrane insertion of GluN2A protein in dendrites was directly observed and shown to depend on a 3' untranslated region cytoplasmic polyadenylation element and its associated translation complex. These findings uncover a novel mechanism for cytoplasmic polyadenylation element-mediated posttranscriptional regulation of GluN2A mRNA to control NMDA receptor surface expression during synaptic plasticity.

GluN2A protein levels and surface expression within dendrites are regulated by both somatic and dendritic protein synthesis. (1) Under basal conditions, dendritic GluN2A levels are regulated by constitutive protein synthesis in the soma. Somatic GluN2A is trafficked into dendrites, likely in the form of post-Golgi vesicles, where it is either inserted in the membrane or held in reserve for subsequent regulation (blue arrows). The post-transcriptional mechanisms regulating somatic GluN2A synthesis remain unclear. (2) Following synaptic activation, intracellular signaling (dashed line) induces the local translation of GluN2A mRNA that is regulated by the CPEB-associated complex in dendrites, resulting in the dendritic synthesis and membrane insertion of GluN2A-containing NMDA receptors, likely via components of a dendritic secretory pathway.